1. Field of the Invention
This invention relates generally to diarylmethyl piperazine compounds having utility in medical therapy especially as receptor-binding species, e.g., as conjugates in agonist/antagonist pairs for verifying/assaying receptor and neurotransmitter function. The compounds of the invention are useful as opioid receptor compounds having utility in treatment of pain, combatting drug addiction, alcohol addiction, drug overdose, mental illness, urinary incontinence, cough, lung edema, emesis, diarrhea, depression, and cognitive, respiratory, and gastro-intestinal disorders. The invention also relates to pharmaceutical formulations of such compounds, methods of treating certain disorders with such compounds, and processes by which such compounds may be prepared.
2. Description of the Related Art
In the study of opioid biochemistry, a variety of endogenous opioid compounds and non-endogenous opioid compounds has been identified. In this effort, significant research has been focused on understanding the mechanism of opioid drug action, particularly as it relates to cellular and differentiated tissue opiate receptors.
Opioid drugs typically are classified by their binding selectivity in respect of the cellular and differentiated tissue receptors to which a specific drug species binds as a ligand. These receptors include mu (.mu.), delta (.delta.), sigma (.sigma.) and kappa (.kappa.receptors.
The well-known narcotic opiates, such as morphine and its analogs, are selective for the opiate mu receptor. Mu receptors mediate analgesia, respiratory depression, and inhibition of gastrointestinal transit. Kappa receptors mediate analgesia and sedation. Sigma receptors mediate various biological activities.
The existence of the opioid delta receptor is a relatively recent discovery which followed the isolation and characterization of endogenous enkephalin peptides which are ligands for the delta receptor. Research in the past decade has produced significant information about the delta receptor, but a clear picture of its function has not yet emerged. Delta receptors mediate analgesia, but do not appear to inhibit intestinal transit in the manner characteristic of mu receptors.
Opioid agents frequently are characterized as either agonists or antagonists. Agonists and antagonists are agents which recognize and bind to receptors, affecting (either initiating or blocking) biochemical/physiological sequences, a process known as transduction. Agonists inhibit or suppress neurotransmitter outputs in tissues containing receptors, e.g., inhibiting pain responses, or affecting other output-related phenomena. Antagonists also bind to receptors, but do not inhibit neurotransmitter outputs. Thus, antagonists bind to the receptor sites and block the binding of agonist species which are selective for the same receptor.
Concerning specific receptor ligands, the distinction between delta receptor agonists and antagonists heretofore has been made by their activity in the electrically stimulated mouse vas deferens assay, which typically has been considered the appropriate diagnostic tissue for the delta receptor. By contrast, mu receptor agonists are generally characterized by their activity in the electrically stimulated guinea pig ileum assay.
Only a relatively small number of essentially pure delta receptor-selective agents is known, and with the exception of the delta opioid receptor antagonists disclosed in Portoghese U.S. Pat. No. 4,816,586, all known delta receptor-selective opioid compounds are peptides, including endogenous enkephalins and other endorphins, as well as exogenous peptide analogs. The previously synthesized exogenous peptide analogs have various associated disadvantages in terms of their stability, their potentially suitable delivery routes as administered drug agents, and their in vivo tissue distribution.
Various physiological effects of the known peptide-based opioid ligands have been studied, including: analgesia; respiratory depression; gastrointestinal effects; mental, emotional, and cognitive process function; and mediation/modulation of other physiological processes.
The aforementioned U.S. Pat. No. 4,816,586, issued Mar. 28, 1989 to P. S. Portoghese, discloses various delta-opioid receptor antagonists of specified formula. The disclosed antagonist compounds are formed by fusion of an indole, benzofuran, benzopyrazine, or quinoline ring system, to the C-ring of naltrexone. These compounds are described as possessing a unique opioid receptor antagonist profile, including compounds which are highly selective for the delta opioid receptor.
U.S. Pat. No. 4,518,711 issued May 21, 1985 to V. J. Hruby et al. describes cyclic, conformationally constrained analogs of enkephalins. These compounds include both agonists and antagonists for the delta receptor.
In addition to the above-described references relating to opioid compounds, the art relevant to the compounds of the present invention includes the polyaryl piperazine compounds described in the various references identified below.
S. Goenechea, et al., in "Investigation of the Biotransformation of Meclozine in the Human Body," J. Clin. Chem. Clin. Biochem., 1988 26(2), 105-15, describe the oral administration of a polyaryl piperazine compound in a study of meclozine metabolization in human subjects.
In "Plasma Levels, Biotransformation and Excretion of Oxatomide in Rats, Dogs, and Man," Meuldermans, W., et al., Xenobiotica, 1984, 15(6), 445-62, there is disclosed a metabolic study of plasma levels, biotransformation, and excretion of oxatomide.
T. Iwamoto, et al., in "Effects of KB-2796, A New Calcium Antagonist, and Other Diphenylpiperazines on [.sup.3 H]nitrendipine Binding," Jpn. J. Pharmacol., 1988, 48(2), 241-7, describes the effect of a polyaryl piperazine of specified formula, as a calcium antagonist.
K. Natsuka, et al., in "Synthesis and Structure-Activity Relationships of 1-Substituted 4-(1,2-Diphenylethyl)piperazine Derivatives Having Narcotic Agonist and Antagonist Activity," J. Med. Chem., 1987, 30 (10), 1779-1787, disclose racemates and enantiomers of 1-substituted 4-[2-(3-hydroxyphenyl)-1-phenylethyl]piperazine derivatives.
European Patent Application No. 458,160 published 27 Nov. 1991 describes substituted diphenylmethane derivatives which are said to be useful as analgesic and antiinflammatory agents, including compounds wherein the methylene bridging group (linking the two phenyl moieties) may have as a substituent on the methylene carbon a piperidinyl or piperazinyl group.
South African Patent Application No. 8604522 published 17 Dec. 1986 discloses N-substituted arylalkyl and aryl-alkylene substituted amino-heterocylic compounds, including piperidine derivatives, which are described as useful cardiovascular, antihistamine, and anti-secretory agents.
European Patent Application No. 133,323 published 20 Feb. 1985 discloses certain diphenylmethyl piperazine compounds useful as non-sedative antihistamines.
There is a continuing need in the art for improved opioid compounds, particularly compounds which are free of adverse side effects of conventional opiates such as morphine and pethidine.